This invention relates to P-chiral bisphospholane ligands and methods for their preparation. In addition, this invention relates to the formation of metal/P-chiral bisphospholane complexes that catalyze asymmetric transformation reactions to generate high enantiomeric excesses of formed compounds.
There is a growing trend in the pharmaceutical industry to market chiral drugs in enantiomerically pure form in order to provide desired positive effects in humans. Production of enantiomerically pure compounds is important for several reasons. First, one enantiomer often provides a desired biological function through interactions with natural binding sites, but another enantiomer typically does not have the same function or effect. Further, it is possible that one enantiomer has harmful side effects, while another enantiomer provides a desired positive biological activity. To meet this demand for chiral drugs, many approaches for obtaining enantiomerically pure compounds have been explored such as diastereomeric resolution, structural modification of naturally occurring chiral compounds, asymmetric catalysis using synthetic chiral catalysts and enzymes, and the separation of enantiomers using simulated moving bed (SMB) technology.
Asymmetric catalysis is often the most efficient method because a small amount of a chiral catalyst can be used to produce a large quantity of a chiral target molecule. Over the last two decades, more than a half-dozen commercial industrial processes have been developed that use asymmetric catalysis as the key step in the production of enantiomerically pure compounds with a tremendous effort focused on developing new asymmetric catalysts for these reactions (Morrison J. D., ed. Asymmetric Synthesis, Academic Press: New York, 1985:(5); Bosnich B., ed. Asymmetric Catalysis, Martinus Nijhoff Publishers: Dordrecht, Netherlands, 1986; Brunner H., Synthesis, 1988:645; Scheffold R., ed. Modern Synthetic Methods, Springer-Verlag: Berlin Hedelberg, 1989;115(5); Nugent W. A., RajanBabu T. V., Burk M. J., Science, 1993;259:479; Ojima I., ed. Catalytic Asymmetric Synthesis, VCH: New York, 1993; Noyori R., Asymmetric Catalysis In Organic Synthesis, New York: John Wiley and Sons, Inc., 1994).
Chiral phosphine ligands have played a significant role in the development of novel transition metal catalyzed asymmetric reactions to produce enantiomeric excess of compounds with desired activities. The first successful attempts at asymmetric hydrogenation of enamide substrates were accomplished in the late 1970""s using chiral bisphosphines as transition metal ligands (Vineyard B. D., Knowles W. S., Sabacky M. J., Bachman G. L., Weinkauff D. J., J. Am. Chem. Soc., 1977;99(18):5946-5952; Knowles W. S., Sabacky M. J., Vineyard B. D., Weinkauff D. J., J. Am. Chem. Soc., 1975;97(9):2567-2568).
Since these first published reports, there has been an explosion of research geared toward the synthesis of new chiral bisphosphine ligands for asymmetric hydrogenations and other chiral catalytic transformations (Ojima I., ed. Catalytic Asymmetric Synthesis, VCH Publishers, Inc., 1993; Ager D. J., ed. Handbook of Chiral Chemicals, Marcel Dekker, Inc., 1999). Highly selective rigid chiral phospholane ligands have been used to facilitate these asymmetric reactions. For example, phospholane ligands are used in the asymmetric hydrogenation of enamide substrates and other chiral catalytic transformations.
BPE, Duphos, and BisP ligands are some of the most efficient and broadly useful ligands developed for asymmetric hydrogenation to date. Burk M. J., Chemtracts 11(11), 787-802 (CODEN: CHEMFW ISSN:1431-9268. CAN 130:38423; AN 1998:698087 CAPLUS) 1998; Burk M. J., Bienewald F., Harris M., Zanotti-Gerosa A., Angew. Chem., Int. ed., 1998;37(13/14):1931-1933; Burk M. J., Casy G. Johnson N. B., J. Org. Chem., 1998;63(18):6084-6085; Burk M. J., Kalberg C. S., Pizzano A., J. Am. Chem. Soc., 1998;120(18):4345-4353; Burk M. J., Harper T. G. P., Kalberg C. S., J. Am. Chem. Soc., 1995;117(15):4423-4424; Burk M. J., Feaster J. E., Nugent W. A., Harlow R. L., J. Am. Chem. Soc., 1993;1 15(22):10125-10138; Nugent W. A., RajanBabu T. V., Burk M. J., Science (Washington, D. C., 1883-) 1993;259(5094):479-483; Burk M. J., Feaster J. E., Harlow R. L., Tetrahedron: Asymmetry, 1991;2(7):569-92; Burk M. J., J. Am. Chem. Soc., 1991;113(22):8518-8519; Imamoto T., Watanabe J., Wada Y., Masuda H., Yamada H., Tsuruta H., Matsukawa S., Yamaguchi K., J. Am. Chem. Soc., 1998;120(7):1635-1636; Zhu G., Cao P., Jiang Q., Zhang X., J. Am. Chem. Soc., 1997;119(7): 1799-1800. For example, a Rhodium/Duphos complex can be used to selectively form (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, known as pregabalin, which is used as an anti-seizure drug. The S-enantiomer, which is produced in an enantiomeric excess, is preferred because it shows better anticonvulsant activity than the R-enantiomer. Yuen et al., Bioorganic and Medicinal Chemistry Letters, 1994;4:823.
The success of BPE, DuPhos, and BisP transition metal complexes in asymmetric hydrogenations is derived from many factors. For example, substrate to catalyst ratios of up to 50,000/1 have been demonstrated. Also, high rates of substrate conversion to product using low hydrogen pressures have been observed with catalysts made from these ligands.
BPE, Duphos, and BisP have shown high enantioselectivities in numerous asymmetric reactions. Improved reaction of BPE, Duphos, and BisP is attributed to, among other factors, rigidity in their C2-symmetric structure. If the spatial area of a metal/phosphine ligand structure, such as BPE, is divided into four quadrants, as shown in Scheme 1, alternating hindered and unhindered quadrants are formed. 
This structural feature creates areas of hindrance in the metal complexes and produces desired stereochemical results in asymmetric hydrogenation reactions. However, there are a variety of reactions, such as catalysis of simple olefins, in which these ligands are not very efficient in terms of activity and selectivity.
Further, there are many characteristics associated with these ligands, which may limit their application. For example, the chiral center of these ligands is not directly bonded to the metal center. This may reduce the effectiveness of enantioselectivity in asymmetric reactions because the chirality of the ligands helps direct the stereochemistry during the reaction of a target molecule with the metal/chiral ligand complex. Therefore, bonding a chiral atom closer to the metal center may increase the formation of enantiomeric excesses. Also, bulky substituents in the unhindered regions may limit the availability and reactivity of the metal center to the target molecule.
Improved chiral phosphine ligands are needed that can further improve the production of enantiomerically active forms of compounds through asymmetric catalysis. Thus, there is a need to develop methods for the production of and to synthesize compounds that bond a chiral phosphine atom directly to a metal center and remove prohibitive substituents from the ligand to improve enantioselectivity in asymmetric reactions.
The present invention provides for P-chiral bisphospholane ligand enantiomers and methods for their preparation. P-chiral bisphospholanes when complexed with a metal, serve as catalysts in asymmetric hydrogenation reactions to facilitate the formation of a desired stereoisomer. A P-chiral bisphospholane compound of the present invention is represented by the structural Formula I: 
wherein:
R is an alkyl, fluoroalkyl or perfluoroalkyl group each containing up to about 8 carbon atoms, a carboxylic acid group, a carboxylic ester group, an aryl group, a substituted aryl group, an aralkyl group, or a ring substituted aralkyl group; and
a Bridge is a xe2x80x94(CH2)nxe2x80x94 where n is an integer from 1 to 12, a 1,2-divalent phenyl, or a 1,2-divalent substituted phenyl. The corresponding enantiomer of Compound I is another compound of the present invention.
Another P-chiral bisphospholane compound of the present invention has the structural Formula VII: 
wherein:
R is an alkyl, fluoroalkyl, or perfluoroalkyl group each containing up to about 8 carbon atoms, a carboxylic acid group, a carboxylic ester group, an aryl group, a substituted aryl group, an aralkyl group, or a ring substituted aralkyl group; and
each Y is independently halogen, alkyl, alkoxy, aryl, aryloxy, nitro, amino, vinyl, substituted vinyl, alkynyl, or sulfonic acid, and n is an integer from 0 to 4 equal to the number of unsubstituted aromatic ring carbons. The corresponding enantiomer of general Compound VII is another compound of the present invention.
Compounds formed during the synthesis of P-chiral bisphospholane ligands include compounds with the structural Formulae V and VIa and their corresponding enantiomers: 
wherein:
R is an alkyl, fluoroalkyl, or perfluoroalkyl group each containing up to about 8 carbon atoms, a carboxylic acid group, a carboxylic ester group, an aryl group, a substituted aryl group, an aralkyl group, or a ring substituted aralkyl group; and
G is an alkyl group containing up to about 12 carbon atoms, NRxe2x80x22, ORxe2x80x2, SRxe2x80x2, or SiMe3, wherein Rxe2x80x2 is hydrogen, an alkyl, aryl, substituted aryl, an aralkyl group; or a ring substituted aralkyl group. 
wherein:
R is an alkyl, fluoroalkyl, or perfluoroalkyl group each containing up to about 8 carbon atoms, a carboxylic acid group, a carboxylic ester group, an aryl group, a substituted aryl group, an aralkyl group, or a ring substituted aralkyl group; and
a Bridge is a xe2x80x94(CH2)nxe2x80x94 where n is an integer from 1 to 12, a 1,2-divalent phenyl, or a 1,2-divalent substituted phenyl.
Other intermediates formed in alternative synthetic routes to P-chiral phospholanes are compounds with the structural Formulae Vb and VIb: 
wherein:
R is an alkyl, fluoroalkyl, or perfluoroalkyl group each containing up to about 8 carbon atoms, a carboxylic acid group, a carboxylic ester group, an aryl group, a substituted aryl group, an aralkyl group, or a ring substituted aralkyl group;
G is an alkyl group containing up to about 12 carbon atoms; NRxe2x80x22, ORxe2x80x2, SRxe2x80x2, or SiMe3, wherein Rxe2x80x2 is hydrogen, an alkyl, aryl, substituted aryl, an aralkyl group; or a ring substituted aralkyl group;
X is S or O; and
a Bridge is a xe2x80x94(CH2)nxe2x80x94 where n is an integer from 1 to 12, a 1,2-divalent phenyl, or a 1,2-divalent substituted phenyl.
Another aspect of the invention is directed to methods for forming P-chiral bisphospholane ligands. The methods include preparing a compound of Formula I through several intermediates, as shown in Schemes 3 and 4. One method, for example, includes steps of reacting a bulky alkoxy compound, such as (xe2x88x92)-menthol, with phosphorous trichloride to form a first intermediate of the Formula IIa. The first intermediate is reacted with a divalent alkyl di-Grignard solution and a borane methyl sulfide complex to form a second intermediate with, for example, the Formula IIIa. The second intermediate is then reacted with a chiral base, for example, s-butyl lithium/(xe2x88x92)-sparteine, and an electrophile for enantioselective alkylation of the second intermediate to form a third intermediate, such as IVa. The third intermediate is reacted with methyl anion, such as methyl lithium, to form a fourth intermediate with, for example, the structural Formula Va. The fourth intermediate is then reacted with an oxidative coupling agent to form a fifth intermediate, such as VIa. Compound VIa can be reacted with a borane removing mixture, as depicted n Scheme 4, to form a compound with the structural Formula I or its corresponding enantiomer.
Another aspect of the invention is directed to methods for forming P-chiral bisphospholane ligand intermediates, such as a compound of Formula 17, through the use of intermediate compounds shown in Schemes 12 and 13.
Another aspect of the invention is directed to methods for forming P-chiral bisphospholane ligands, such as a compound of Formula I through the use of intermediate compounds shown in Schemes 9 and 10.
Another aspect of the invention is directed to methods for forming a compound of the Formula VII through intermediate compounds, as depicted in Scheme 6. For example, a bis(primary phosphine) is reacted in the presence of a strong base with a cyclic sulfate compound to form a first compound that is then reacted with a chiral base and electrophile for enantioselective alkylation of the first compound to form a second compound. The second compound is reacted with a borane removing mixture to form a compound of the Formula VII or its corresponding enantiomer.
Another compound of the present invention has the structural Formula IX: 
wherein:
R is an alkyl, fluoroalkyl, or perfluoroalkyl group each containing up to about 8 carbon atoms, a carboxylic acid group, a carboxylic ester group, an aryl group, a substituted aryl group, an aralkyl group, or a ring substituted aralkyl group;
a Bridge is a xe2x80x94(CH2)n- where n is an integer from 1 to 12, a 1,2-divalent phenyl, or a 1,2-divalent substituted phenyl;
M is a transition metal, an actinide, or a lanthanide;
Z is BF4, PF6, SbF6, OTf, or ClO4; and
A is norbornadiene or cyclooctadiene.
The corresponding enantiomer of general Compound IX is another compound of the present invention.
Another aspect of the invention is directed to methods for forming compounds of the Formula IX, such as IXc, as shown, for example, in Scheme 11.
Yet another aspect of the invention is directed to forming compounds with high enantiomeric excesses in catalytic asymmetric transformations using metal/P-chiral bisphospholane complexes of the structural Formula IX.
The present invention is related to the synthesis of P-chiral bisphospholane ligands for preparing metal/P-chiral bisphospholane complexes for asymmetric catalysis. In this application, xe2x80x9cP-chiralxe2x80x9d means that the phosphorous atom or atoms of a compound are chiral centers of that compound. In particular, the present invention is directed to reacting the metal/P-chiral bisphospholane complexes with, for example, acrylates, in asymmetric hydrogenation syntheses to produce enantiomeric excesses of compounds. While the present invention is not so limited, an appreciation of various aspects of the invention will be gained through a discussion of the examples provided below.
For the purpose of this application, the xe2x80x9ccorresponding enantiomerxe2x80x9d means that if a compound includes two P-chiral centers and two C-chiral or chiral carbon atom centers, the xe2x80x9ccorresponding enantiomerxe2x80x9d for a compound having an 1R,2S configuration is the 1S,2R compound. Similarly, if a compound has an 1S,2R configuration, the xe2x80x9ccorresponding enantiomerxe2x80x9d is the 1R,2S compound. If a P-chiral compound has an 1S,2S configuration, the xe2x80x9ccorresponding enantiomerxe2x80x9d is the 1R,2R compound. If a P-chiral compound has an 1R,2R configuration, the xe2x80x9ccorresponding enantiomerxe2x80x9d is the 1S,2S compound. Phosphorous chiral centers are designated as 1 and carbon chiral centers are designated as 2 in bisphospholanes.
For the purpose of this application, a xe2x80x9ccompound with a high degree of enantiomeric purity,xe2x80x9d a xe2x80x9ccompound of high enantiomeric purity,xe2x80x9d or a xe2x80x9chigh level of enantioselectivityxe2x80x9d means a hydrogenation that yields a product of greater than or equal to about 80 percent enantiomeric excess (abbreviated e.e.).
Enantiomeric excess is defined as the ratio (% Rxe2x88x92% S)/(% R+% S)*100, where % R is the percentage of R enantiomer and % S is the percentage of S-enantiomer in a sample of optically active compound.
P-Chiral Phospholanes
The present invention provides novel P-chiral bisphospholane substituted compounds of the structural Formula I and its corresponding enantiomer: 
wherein:
R is an alkyl, fluoroalkyl, or perfluoroalkyl group each containing up to about 8 carbon atoms, a carboxylic acid group, a carboxylic ester group, an aryl group, a substituted aryl group, an aralkyl group, or a ring substituted aralkyl group; and
a Bridge is a xe2x80x94(CH2)nxe2x80x94 where n is an integer from 1 to 12, a 1,2-divalent phenyl, or a 1,2-divalent substituted phenyl.
The term xe2x80x9calkyl,xe2x80x9d as used in this application includes a straight or branched saturated aliphatic hydrocarbon chain, or cyclic saturated aliphatic hydrocarbons, such as, for example, methyl, ethyl, propyl, isopropyl (1-methylethyl), butyl, tert-butyl (1,1-dimethylethyl), cyclohexyl, cyclopentyl, cyclobutyl, and the like.
The term xe2x80x9cfluoroalkyl,xe2x80x9d as used in this application includes an alkyl, wherein alkyl is defined above, having one or more hydrogen atoms substituted by fluorine atoms.
The term xe2x80x9cperfluoroalkyl,xe2x80x9d as used in this application, includes an alkyl, wherein alkyl is defined above, having all hydrogen atoms substituted by fluorine atoms.
The term xe2x80x9carylxe2x80x9d group, as used in this application, includes an aromatic hydrocarbon group, including fused aromatic rings, such as, for example, phenyl and naphthyl. Such groups may be unsubstituted or independently substituted on the aromatic ring by, for example, halogen, alkyl, alkoxy, aryl, aryloxy, nitro, amino, vinyl, substituted vinyl, alkynyl, or sulfonic acid.
The term xe2x80x9caralkylxe2x80x9d group, as used in this application, includes one or more aryl groups, as defined above, bonded to an alkyl group, for example, benzyl, with the alkyl bonded to the phospholane ring. The aromatic hydrocarbon group may be unsubstituted or substituted (ring substituted aralkyl) by, for example, an alkoxy group of 0 to 4 carbon atoms, an amino group, a hydroxy group, or an acetyloxy group.
The term xe2x80x9csubstituted phenyl,xe2x80x9d as used in this application, includes a phenyl group with the unsubstituted aromatic ring carbons independently substituted by, for example, halogen, alkyl, alkoxy, aryl, aryloxy, nitro, amino, vinyl, substituted vinyl, alkynyl, or sulfonic acid.
The term xe2x80x9ccarboxylic ester,xe2x80x9d as used in this application, includes a COO group bonded through one oxygen atom to an alkyl, an aryl, or a substituted aryl, wherein alkyl, aryl, and substituted aryl are described above, and the carbon atom bonded to the phospholane ring.
The term xe2x80x9cphospholane ring,xe2x80x9d as used in this application, includes a 5-membered cyclic structure in which at least one atom is phosphorous.
The term xe2x80x9ctransition metal,xe2x80x9d as used in this application, includes scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, lanthanum, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, and gold.
The term xe2x80x9cactinide,xe2x80x9d as used in this application includes thorium, protactinium, uranium, neptunium, plutonium, americium, curium, berkelium, californium, einsteinium, fermium, mendelevium, nobelium, and lawrencium.
The term xe2x80x9clanthanide,xe2x80x9d as used in this application includes cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, and lutetium.
The bisphospholane compounds of Formula I are disubstituted with an R group bonded to one of the carbons of the phospholane ring and a bridging group bonded between the phosphorus on the phospholane rings. The compounds lack an R group in the unhindered quadrant of the phospholane ring, as shown in Scheme 2. 
The P-chiral bisphospholane locates chirality closer to the metal center than in known metal/phospholane complexes, such as Duphos and BisP. The chiral center""s closer proximity to the metal may produce greater enantioselectivity in the end-products. Also, the lack of substituents in the unhindered quadrants of Formula I compounds may improve the availability of the metal center for catalysis.
Typical R groups include, but are not limited to, for example, lower alkyl groups such as methyl, ethyl, and isopropyl, along with bulkier groups such as benzhydryl, fluorenyl, and trityl groups. One typical R group for compounds of Formula I are aralkyl groups, such as a benzyl group. Examples of other P-chiral bisphospholane ligands include, but are not limited to, 1,2-bis((1S,2S)-2-benzylphospholano)-ethane, 1,2-bis((1R,2R)-2-benzylphospholano)-ethane, 1,2-bis((1S,2R)-2-methylphospholano)-ethane, 1,2-bis((1S,2R)-2-ethylphospholano)-ethane. Examples of enantiomers of the P-chiral phospholane ligands of I include, but are not limited to, 1,2-bis((1R,2S)-2-methylphospholano)-ethane, and 1,2-bis((1R,2S)-2-ethylphospholano)-ethane.
The P-chiral bisphospholane substituted compound, 1,2-bis((1R,2R)-2-benzylphospholano)-ethane, is represented by the Formula Ia: 
The P-chiral bisphospholane substituted compound, 1,2-bis((1S,2S)-2-benzylphospholano)-ethane, is represented by the Formula Ib: 
The bisphospholane ligands of the structural Formula I are capable of reacting with transition metals, actinides, or lanthanides to form complexes for use in asymmetric catalysis. The use of these compounds as ligands for transition metals results in catalysts that yield a high level of enantioselective and stereochemical control in the catalyzed hydrogenation of unsaturated substrates.
Several intermediates are formed during the synthesis of compounds of the Formula I. This invention includes intermediate compounds of the formulae V and VIa and their corresponding enantiomers: 
wherein:
R is an alkyl, fluoroalkyl, or perfluoroalkyl group each containing up to about 8 carbon atoms, a carboxylic acid group, a carboxylic ester group, an aryl group, a substituted aryl group, an aralkyl group, or a ring substituted aralkyl group; and
G is an alkyl group containing up to about 12 carbon atoms, NRxe2x80x22, ORxe2x80x2, SRxe2x80x2, or SiMe3, wherein Rxe2x80x2 is hydrogen, an alkyl, aryl, substituted aryl, an aralkyl group; or a ring substituted aralkyl group. 
R is an alkyl, fluoroalkyl, or perfluoroalkyl group each containing up to about 8 carbon atoms, a carboxylic acid group, a carboxylic ester group, an aryl group, a substituted aryl group, an aralkyl group, or a ring substituted aralkyl group; and
a Bridge is a xe2x80x94(CH2)n- where n is an integer from 1 to 12, a 1,2-divalent phenyl, or a 1,2-divalent substituted phenyl.
Chiral ligands of the structural Formula I can alternatively be prepared through intermediates with the structural formulae Vb and VIb: 
wherein:
R is an alkyl, fluoroalkyl, or perfluoroalkyl group each containing up to about 8 carbon atoms, a carboxylic acid group, a carboxylic ester group, an aryl group, a substituted aryl group, an aralkyl group, or a ring substituted aralkyl group;
G is an alkyl group containing up to about 12 carbon atoms, NRxe2x80x22, ORxe2x80x2, SRxe2x80x2, or SiMe3, wherein Rxe2x80x2 is hydrogen, an alkyl, aryl, substituted aryl, an aralkyl group; or a ring substituted aralkyl group;
X is S or O; and
a Bridge is a xe2x80x94(CH2)n- where n is an integer from 1 to 12, a 1,2-divalent phenyl, or a 1,2-divalent substituted phenyl.
Another compound of the present invention has the structural Formula VII: 
wherein:
R is an alkyl, fluoroalkyl, or perfluoroalkyl group each containing up to about 8 carbon atoms, a carboxylic acid group, a carboxylic ester group, an aryl group, a substituted aryl group, an aralkyl group, or a ring substituted aralkyl group; and
each Y is independently halogen, alkyl, alkoxy, aryl, aryloxy, nitro, amino, vinyl, substituted vinyl, alkynyl, or sulfonic acid and n is an integer from 0 to 4 equal to the number of unsubstituted aromatic ring carbons.
The above bisphospholane compounds of Formulae I and VII and their corresponding enantiomers can be complexed with any of the transition metals as well as the lanthanides and actinides. Such complexes are formed by methods known in the art.
Another compound of the present invention includes the metal/P-chiral phospholane complex with the structural Formula IX and its corresponding enantiomer: 
wherein:
R is an alkyl, fluoroalkyl, or perfluoroalkyl group each containing up to about 8 carbon atoms, a carboxylic acid group, a carboxylic ester group, an aryl group, a substituted aryl group, an aralkyl group, or a ring substituted aralkyl group;
a Bridge is a xe2x80x94(CH2)n- where n is an integer from 1 to 12, a 1,2-divalent phenyl, or a 1,2-divalent substituted phenyl;
M is a transition metal, an actinide, or a lanthanide;
Z is BF4, PF6, SbF6, OTf, or ClO4; and
A is norbornadiene or cyclooctadiene.
Z can also be any other appropriate counterion. The anion OTfxe2x88x92 is triflate.
Typically useful transition metal complexes of the present invention are those including the above described compounds complexed with rhodium.
Synthesis of Borane-Protected Bisphospholanes
Chiral ligands of the structural Formula I can be prepared as shown in Schemes 3 and 4. 
The synthesis route to one of the borane-protected bisphospholane of the Formula VIa is shown in Scheme 3. A chiral menthoxy group is used in this synthesis. The chirality of the menthoxy group is not required in the synthesis, and different alkoxy substituents (chiral and achiral) can be used to accomplish the synthesis of the compounds of the Formula I. For example, an alcohol of the formula R1OH wherein R1 is a branched alkyl, an aryl group, a substituted aryl group, an aralkyl group, a ring substituted aralkyl group or other bulky group. For example, adamantyl and phenyl are suitable R1 substituents. Reaction of (xe2x88x92)-menthol with phosphorous trichloride in tetrahydrofuran produces (xe2x88x92)-menthoxyphosphorous dichloride, shown with the structural Formula IIa in Scheme 3. (+)-Menthol is also suitable for this reaction. An example of an alternative compound for reacting with (xe2x88x92)-menthol includes PBr3. A phosphine-borane compound of the Formula IIIa, can be formed by reacting (xe2x88x92)-menthoxyphosphorous dichloride with a divalent alkyl di-Grignard solution, shown in Scheme 3, and then a borane complex. Examples of borane complexes include, but are not limited to, a borane methylsulfide complex or alternatively a borane tetrahydrofuran complex, which are commercially available from Aldrich Chemical Co.
The enantioselective alkylation of the phosphine-borane Compound IIIa is performed using a chiral base formed from s-BuLi and (xe2x88x92)-sparteine (Imamoto T., Watanabe J., Wada Y., Masuda H., Yamada H., Tsuruta H., Matsukawa S., Yamaguchi K., J. Am. Chem. Soc., 1998;120(7):1635-1636; Muci A. R., Campos K. R., Evans D. A., J. Am. Chem. Soc., 1995;117(35):9075-9076. Other suitable chiral bases can be used to provide improved enantioselectivities for the chiral alkylation reactions or to form the desired enantiomer, such as compounds having the general formula R3Li wherein R3 is an alkyl, an aryl, an alkylamide, or an alkylamine. Compound IVa was synthesized via this chiral alkylation procedure. Selectivity is determined by two factors: the xcex1-carbon atom from which the proton is pulled and the face of the ring at which the resulting anion is alkylated. A proton is pulled selectively from one carbon atom of the phosphine ring using the chiral base. The alkylation occurs selectively on the same side of the ring occupied by the borane group.
The electrophile added for the chiral alkylation can be any electrophile including, but not limited to, an alkyl halide, carbon dioxide, an aldehyde, a ketone, a carboxylic ester, a carbonate, a silyl chloride, or an alkyl sulfonate to form a compound of the Formula IVa as a third intermediate having the group R, wherein R is an alkyl, fluoroalkyl, or perfluoroalkyl group each containing up to about 8 carbon atoms, a carboxylic acid group, a carboxylic ester group, an aryl group, a substituted aryl group, an aralkyl group, or a ring substituted aralkyl group. Examples of suitable electrophiles include, but are not limited to, benzyl bromide, iodomethane, iodoethane, carbon dioxide, chlorotrimethylsilane, benzaldehyde, acetone, cyclopentanone, benzophenone, ethyl acetate, dimethyl carbonate, or di-tert-butyl dicarbonate. The electrophile can be varied to synthesize a variety of ligands that possess different substituents on the phospholane ring to match the steric requirements for producing a specific enantiomer of the target molecules.
The relative stereochemistry of compounds of the structural Formula IVa was assigned by analogy to the crystal structure of the IVa compound wherein R is CO2H. Apparently, the bulkiness of the menthoxy group blocks the approach of the electrophile from the bottom face of the ring. Therefore, during an alkylation of the bisphospholane, IIIa, without the use of a chiral base, predominantly only 2 diastereomers are formed.
Although the diastereomeric excess of the alkylated products IVa could not be evaluated before displacing the menthoxy group with methyl lithium, the enantiomeric excess of compounds Va could be determined. The values of the enantiomeric excesses ranged from low to mid 70 percent. The relative stereochemistry of Compound Va, wherein R is a benzyl group, was determined via Nuclear Overhauser effect (NOE) studies. The relative stereochemistry of other compounds of the Formula Va, wherein R is either a methyl or an ethyl, was assigned by analogy.
In the synthesis of Compound Va, methyl lithium displaces the menthoxy group with retention of configuration at phosphorous rather than inversion. Other methyl anions can be used to displace the menthoxy group, such as methyl magnesium bromide or methyl cuprate. Had the stereochemistry at phosphorous been inverted, the R groups of Compound I ligands would then reside on the opposite side of the phospholane ring with respect to the lone pairs of electrons on the phosphorous producing the opposite diastereomer. High enantioselectivity would not be expected when using the metal complexes of these ligands in asymmetric hydrogenation were this the case.
The oxidative coupling of Va results in an amplification of the enantiomeric excess of the chiral borane protected product VIa. One oxidative coupling agent reaction includes reacting Va with, for example, s-BuLi and CuCl2. Alternative oxidative coupling reagents include strong bases, such as s-BuLi in conjunction with various copper(II) salts including, but not limited to CuBr2, CuI2, or Cu(OTf)2, Cu(OPiv)2. Piv means pivolate. The minor enantiomer of Va reacts predominantly with the major enantiomer to form a meso complex, which can be removed from the reaction mixture by recrystallization. Before work-up of the reaction, Compound VIa exists in less than 100% enantiomeric excess. After recrystallization, VIa is made optically pure. Alternatively, the borane protected ligand of the structural Formula VIa can be synthesized via the route shown in Scheme 5. 
The compound of Formula Xa can be synthesized via the route shown in Scheme 6. 
As depicted in Scheme 6, a bis(primary phosphine) is reacted with a strong base capable of deprotonating a Pxe2x80x94H. For example, 1,2-bis(phosphino)benzene can be reacted with the strong base. Suitable bases include, but are not limited to, sodium amide, potassium hydroxide, sodium hydroxide or compounds with a structural formula R3Li, wherein R3 is an alkyl, an aryl, an alkylamide, or an alkylamine. For example, methyl lithium, n-butyl lithium, phenyl lithium, or lithium diisopropylamide can be used to deprotonate the Pxe2x80x94H bond. The strong base removes one proton from the phosphorous atom of each primary phosphine group, forming an anion. The anion is reacted with a cyclic sulfate, shown in Scheme 6, to form a carbon-phosphorous bond on each of the phosphorous atoms. Additional base is then added to remove the remaining proton on each of the phosphorous atoms and a heterocyclic phospholane, a first compound, is formed through a second-carbon-phosphorous bond via sulfate group displacement.
The synthesis of Compound Xa was performed via chiral alkylation. The enantioselective alkylation is performed using a chiral base formed from s-BuLi and (xe2x88x92)-sparteine. Imamoto T., Watanabe J., Wada Y., Masuda H., Yamada H., Tsuruta H., Matsukawa S., Yamaguchi K., J. Am. Chem. Soc., 1998;120(7):1635-1636; Muci A. R., Campos K. R., Evans D. A., J. Am. Chem. Soc., 1995;117(35):9075-6. Alternatively, other suitable chiral bases can be used to provide improved enantioselectivities for the chiral alkylation reactions or to form the desired enantiomer. The electrophile added for the chiral alkylation can be any electrophile including, but not limited to, an alkyl halide, carbon dioxide, an aldehyde, a ketone, a carboxylic ester, a carbonate, a silyl chloride, or an alkyl sulfonate to form a compound with the structural Formula Xa as a second compound having the group R, wherein R is an alkyl, fluoroalkyl or perfluoroalkyl group each containing up to about 8 carbon atoms, a carboxylic acid group, a carboxylic ester group, an aryl group, a substituted aryl group, an aralkyl group, or a ring substituted aralkyl group. Examples of suitable electrophiles include, but are not limited to, benzyl bromide, iodomethane, iodoethane, carbon dioxide, chlorotrimethylsilane, benzaldehyde, acetone, trisylazide, cyclopentanone, benzophenone, ethyl acetate, dimethyl carbonate, or di-tert-butyl dicarbonate. The electrophile can be varied to synthesize a variety of ligands that possess different substituents on the phospholane ring to match the steric requirements for producing a specific enantiomer of the target molecule.
The chiral alkylation step produces an enantiomerically enriched borane protected ligand. If a chiral base is not used in the chiral alkylation step, the borane protected ligand product will have a 1:2:1 ratio of R:meso:S and will not be enantiomerically enriched.
Referring to compounds VIa and Xa, two different borane removing mixtures can be used for borane removal from phosphorous which do not lead to racemization at the P-chiral center, as shown in Scheme 4. Typically, the borane group can be removed by treating the phosphine borane ligand with HBF4.Me2O followed by hydrolysis with K2CO3. Alternatively, stirring the borane protected ligand, VIa, in toluene with 4 equivalents of DABCO (1,4-diazabicyclo(2.2.2)octane) over 48 hours at 40xc2x0 C. produces the deprotected ligand of the structural Formula I. Borane removal from Compound IXa results in a compound of the Formula VIIa: 
Referring to Scheme 7, upon completion of borane removal, the ligand of the structural Formula I was bound immediately to rhodium by reacting the ligand with (Rh(norbornadiene)BF4)2 to yield a catalyst of Formula IXa. 
Any suitable transition metal, actinide, or lanthanide and corresponding anion can be used to form the metal/P-chiral phospholane complex shown as Compound IX. For example, the corresponding anion can alternatively be PF6xe2x88x92, SbF6xe2x88x92, OTfxe2x88x92, or ClO4xe2x88x92 or any other appropriate counterion.
As shown in Scheme 8, chiral intermediates Vb and VIb can be formed. 
Compound Vb can be oxidatively coupled to produce a compound with the general Formula VIb, wherein the Bridge is xe2x80x94(CH2)nxe2x80x94 where n is 2. For example, Vb can be reacted with s-BuLi and CuCl2 to form VIb. Other suitable oxidative coupling agents include, but are not limited to include strong bases, such as s-BuLi in conjunction with various copper(II) salts including, but not limited to CuBr2, CuI2, Cu(OTf)2, or Cu(OPiv)2.
Asymmetric Transformations with Metal P-Chiral Phospholanes Complexes
Metal/P-chiral phospholane complexes of Formula IX can be used to catalyze hydrogenation and other asymmetric reactions. For example, compounds of Formula IX can be used as catalysts in transformations including, but not limited to, hydrogenation, hydroformylation, xcfx80-allyl palladium coupling, hydrosilation, hydrocyanation, olefin metathesis, hydroacylation, and isomerization of allylamines.
For example, a complex represented by the Formula IXc was used to catalyze the substrate, methylacetamidoacetate in the presence of hydrogen, as shown in Scheme 14. 
Compound IXb is the corresponding enantiomer to Compound IXc. 
Compounds of the structural Formulas IX, IXb, and IXc typically bond to a substrate to be catalyzed through the center, M, of a compound with the structural Formula IXd, its corresponding enantiomer, or solvates thereof 
wherein:
R is an alkyl, fluoroalkyl, or perfluoroalkyl group each containing up to about 8 carbon atoms, a carboxylic acid group, a carboxylic ester group, an aryl group, a substituted aryl group, an aralkyl group, or a ring substituted aralkyl group;
a Bridge is a xe2x80x94(CH2)n- where n is an integer from 1 to 12, a 1,2-divalent phenyl, or a 1,2-divalent substituted phenyl; and
M is a transition metal, an actinide, or a lanthanide.
A solvate of the Formula IXc includes compounds having one or more solvent molecules bonded to the M center. The solvent molecules include, but are not limited to, MeOH, THF, ethanol, isopropanol, acetonitrile, methylene chloride, benzene, toluene, water, ethyl acetate, dioxane, carbon tetrachloride, DMSO, DMF, DMF/water mixtures, supercritical carbon dioxide, alcohol/water mixtures, or any other suitable solvent.
Other intermediates can be used to produce a catalyst of the Formula IX that generate either the (S) or (R) enantiomer of the pregabalin precursor. Referring to Scheme 9, either enantiomer of the dimesylate (5) can be synthesized by the choice of (R) or (S) (2,3-epoxypropyl)benzene. 
The synthesis shown in Scheme 9 can also be accomplished starting from racemic (2,3-epoxypropyl)benzene (1). The enantiomers of the resulting racemic diol (4) can then be separated on a preparatory scale using chiral HPLC. 
Referring to Scheme 10, methylphosphine borane is reacted with a compound of the Formula (5) or (7) to form compounds of the Formula (8) and (9). The cyclic sulfate (7) can be used in place of the dimesylate (5). The resulting phospholane monomer (8) is a compound of intermediate V. Phospholane monomer (8) can be reacted to form a ligand with the Formula Ib through the same or similar synthetic route as described for Compound Va found in Schemes 3 and 4 and described in Examples 14 and 15. Compound (8) or it corresponding enantiomer can be synthesized based upon the choice of the optically pure dimesylate (5) or cyclic sulfate (7). Compound (9) or its corresponding enantiomer is a diastereomer by-product of the phospholane ring forming reactions in Scheme 10. 
Referring to Scheme 11, Compound Ib dissolved in THF is reacted with [Rh(norbornadiene)2]+ BF4xe2x88x92 in a solution of MeOH at a temperature of xe2x88x9215xc2x0 C. The resulting solution was then allowed to warm to room temperature yielding Compound IXc. 
Referring to Scheme 12, a synthetic route depicting a general route to a variety of optically pure dimesylates of the Formula (14) where R is any alkyl group is shown. Either enantiomer of these dimesylates can be synthesized based upon the choice of the appropriate enantiomer of the epoxide starting material. Any terminal epoxide can be resolved using Jacobsen epoxide ring opening kinetic resolution catalysts. These optically pure terminal epoxide catalysts are available from Rhodia ChiRex located in Boston, Mass. 
Referring to Scheme 13, the synthetic route shown applies to the synthesis of a variety of phospholane monomers (and thus a variety of catalysts) where R is any alkyl group. The cyclic sulfate of Formula (16) can be used in place of the dimesylate of Formula (14). Phospholane monomer (17) corresponds to compounds of the Formula V. Compound (17) or it corresponding enantiomer can be synthesized based upon the choice of the optically pure dimesylate (14) or cyclic sulfate (16). Compound (18) or its corresponding enantiomer is a diastereomer by-product of the phospholane ring forming reactions in Scheme 13. One synthetic route to catalyst IX from phospholane monomers (17) is shown partially in Scheme 3 and in Schemes 4 and 7. Either enantiomer of the catalyst IX can be synthesized based upon the choice of the enantiomer of the dimesylate (14) or cyclic sulfate (16). 
For the reaction shown in Scheme 14, conditions were modified to optimize the hydrogenation of methylacetamidoacetate. One mole percent of ligand IXc in MeOH at 30 psi of hydrogen and at room temperature resulted in enantiomeric excesses on the order of about 95 percent in less than 45 minutes.
The same conditions were used for the hydrogenation of other substrates, shown in Schemes 15 and 16. The substrates of Schemes 15 and 16 were converted quantitatively to their hydrogenation products using these described conditions. Enantiomeric excess for the products were 86 percent in Scheme 15 and 76 percent in Scheme 16 with 100 percent conversion in both reactions. 
Asymmetric reduction experiments of the potassium salt of 3-cyano-5-methylhex-3-enoic acid have been run using catalyst IXc to produce a pregabalin precursor, as shown in Scheme 17. The t-butylammonium salt of 3-cyano-5-methylhex-3-enoic acid can also be reacted with catalyst IXc to produce the pregabalin precursor. Other substrates that can be reacted with catalyst IXc to undergo asymmetric reduction to produce additional pregabalin precursors are 3-cyano-5-methylhex-3-enoic acid methyl ester and 3-cyano-5-methylhex-3-enoic acid ethyl ester. The pregabalin precursor can then be converted into pregabalin. Pregabalin is the generic name for (S)-(+)-(Aminomethyl)-5-methylhexanoic acid. Pregabalin is used in the treatment and prevention of seizure disorders, pain, and psychotic disorders. 
The hydrogenation experiments show high enantiomeric excesses and conversion rates of the substrates. Hydrogenation of E/Z mixtures of the potassium salt of 3-cyano-5-methylhex-3-enoic acid gave greater than 93 percent enantiomeric excess of product. Other salts of 3-cyano-5-methylhex-3-enoic acid can undergo asymmetric hydrogenation, such as the t-butylamine salt or any other salt of the acid.
Enantiomeric excess determination of the products from the reductions of substrates was accomplished by acidifying the hydrogenated reaction mixture and then treating the carboxylic acid product with tms-diazomethane to form the methyl ester. The enantiomeric ratios of the methyl ester were analyzed via chiral gas chromatography (GC). The assignment of the stereochemistry of the enantiomers was done by comparison of elution order of the methyl esters.
Referring to Scheme 18, a general reaction scheme is shown for the conversion of a pregabalin precursor, such as the pregabalin precursor shown in Scheme 17, to pregabalin. 
Enantiomerically enriched pregabalin precursor, wherein X+ is K+, Li+, Na+, or t-butylammonium, can be recrystallized to form optically pure material that is converted to pregabalin. The optically pure pregabalin precursor can be converted directly to pregabalin by first hydrogenating the nitrile group with sponge nickel in the presence of hydrogen and then acidifying the resulting mixture with acetic acid.
Materials
THF was either distilled from sodium prior to use or obtained from Aldrich Sure-Seal bottles supplied by Aldrich Chemical Company as 99.9% anhydrous. Dichloromethane (anhydrous, 99.8%) and ether (anhydrous, 99.8%) were used as needed from Aldrich Sure-Seal bottles supplied by Aldrich Chemical Company. (1R,2S,5R)-(xe2x88x92)-Menthol, borane methylsulfide complex (approximately 10-10.2 M), phosphorous trichloride (98%), 1.3M s-BuLi in cyclohexane, (xe2x88x92)-sparteine, benzyl bromide (98%), 1.0M MeLi in THF/cumene, tetrafluoroboric acid-dimethyl ether complex (HBF4.Me2O), trimethylsilyldiazomethane, methyl 2-acetamidoacrylate, 2-acetamidoacrylic acid, and xcex1-acetamidocinnamic acid were obtained from Aldrich Chemical Company. AgBF4 (99%) and Chloronorbornadiene rhodium (I) dimer (99%) were supplied by Strem Chemicals, Incorporated. Hydrogen gas (99.995%) was used from a lecture bottle supplied by Specialty Gas.
Hydrogenations were performed in a Griffin-Worden pressure vessel supplied by Kimble/Kontes. (S)-(2,3-epoxypropyl)benzene (99.9% chemical purity, 98.2% enantiomeric excess) was purchased from Rhodia-Chirex on a custom synthesis contract. Sodium metal (stick, dry, 99%), diethylmalonate (99%), lithium aluminum hydride (powder, 95%), methanesulfonylchloride (99.5+%), triethylamine (99.5%), n-BuLi (2.5M in hexanes), and s-BuLi (1.3 M in cyclohexane) were purchased from Aldrich Chemical Company. AgBF4 (99%) and Chloronorbornadiene rhodium(I) dimer (99%) were supplied by Strem Chemicals, Incorporated. Methylphosphine borane was purchased from Digital Chemical Company on a custom synthesis contract.
Nuclear Magnetic Resonance
400 MHz 1H NMR, 100 MHz 13C NMR, and 162 MHz 31P NMR spectra were obtained on xe2x80x9cBartonxe2x80x9dxe2x80x94a Varian Unity+400 (Inova400 after Aug. 15, 2000) spectrometer equipped with an Auto Switchable 4-Nuclei PFG probe, two RF channels, and a SMS-100 sample changer by Zymark. Spectra were generally acquired near room temperature (21xc2x0 C.), and standard autolock, autoshim and autogain routines were employed. Samples are usually spun at 20 Hz for 1D experiments. 1H NMR spectra were acquired using 45-degree tip angle pulses, 1.0 second recycle delay, and 16 scans at a resolution of 0.25 Hz/point. The acquisition window was typically 8000 Hz from +18 to xe2x88x922 ppm (Reference TMS at 0 ppm), and processing was with 0.2 Hz line broadening. Typical acquisition time is 80 seconds. Regular 13C NMR spectra were acquired using 45xc2x0 tip angle pulses, 2.0 second recycle delay, and 2048 scans at a resolution of 1 Hz/point. Spectral width was typically 25 KHz from +235 to xe2x88x9215 ppm (Reference TMS at 0 ppm). Proton decoupling was applied continuously, and 2 Hz line broadening was applied during processing. Typical acquisition time is 102 minutes. 31P NMR spectra were acquired using 45-degree tip angle pulses, 1.0 second recycle delay, and 64 scans at a resolution of 2 Hz/point. Spectral width was typically 48 KHz from +200 to xe2x88x92100 ppm (Reference 85% Phosphoric Acid at 0 ppm). Proton decoupling was applied continuously, and 2 Hz line broadening was applied during processing. Typical acquisition time is 1.5 minutes.
Mass Spectrometry
Mass Spectrometry was performed on a Micromass Platform LC system operating under MassLynx and OpenLynx open access software. The LC was equipped with a HP1100 quaternary LC system and a Gilson 215 liquid handler as an autosampler. Data was acquired under atmospheric pressure chemical ionization with 80:20 acetonitrile/water as the solvent. Temperatures: probe was 450xc2x0 C., source was 150xc2x0 C. Corona discharge was 3500V for positive ion and 3200V for negative ion.
High Performance Liquid Chromatography
High Performance Liquid Chromatography (HPLC) was performed on a series 1100 Hewlett Packard (now Agilent Technologies) instrument equipped with a manual injector, quaternary pump, and a UV detector. The LC was PC controlled using HP Chemstation Plus Software. Reverse phase HPLC was performed with a 150xc3x974.6 mm BDS-Hypersil-C18 column supplied by Keystone Scientific Incorporated. Reverse phase chiral HPLC was performed using a Chiracel OJ-R column supplied by Chiral Technologies. Normal Phase chiral HPLC was performed using Chiracel OJ, Chiracel OD, Chiracel OD-H, Chiracel AD, and Chiracel AS columns supplied by Chiral Technologies.
Gas Chromatography. Gas Chromatography (GC) was performed on a 110 volt Varian Star 3400 equipped with an FID detector with electrometer, a model 1061 packed/530 micron ID flash injector, a model 1077 split/splitless capillary injector, a relay board that monitors four external events, and an inboard printer/plotter. Gas chromatography was performed using 40 mxc3x970.25 mm Chiraldex G-TA or B-TA columns supplied by Advanced Separation Technologies, Incorporated or a 25 mxc3x970.25 mm Coating CP Chirasil-Dex DB column supplied by Chrompack.
X-Ray Crystallography
X-Ray crystallography was performed on an Enraf Nonius CAD-4 instrument. Cell refinement was done with CAD-4. Data reduction, structure solving, structure refinement, molecular graphics, and preparation of data for publication were done with maXus software.